Author:
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Zanuy Gomara, David; Kotla, Rohith; Nussinov, Ruth; Teesalu, Tambet; Sugahara, Kazuki N.; Alemán Llansó, Carlos; Haspel, Nurit
|
Abstract:
|
Neuropilin-1 (NRP-1) is a hub receptor that plays an essential role in angiogenesis and vascular perme-
ability. It is over-expres sed in the new blood vessels grown by tumor cells and is a target for anti-tumor
treatment s. Peptides that expose the consensus sequence R/K/
XX
R/K at the C-terminus (
C-end rule
or
CendR
peptides) bind to NRP-1 and are internalized into the cell. We used peptide phage display binding
assays and molecular dynamics (MD) simulations to study the potential role of the central residues of
CendR
peptides in binding and activa tion of the NRP-1 receptor. The high stability of RPAR–receptor
domain complex stems from the formation of a characteristic pattern of three hydrogen bonds between
the peptide C-terminus and the residues in the NRP-1 loop III. Any changes in the peptide structure that
fail to preserve this triad result in a less-stable complex. We performed a systematic study of R
XX
R
mutants, where
X
= A/D/S/R/P, in order to test the effect of replacement of A or P on the binding capabil-
ities. Our results, both experimental and computational, show that RRAR, RDAR, RPDR, RPRR and RPPR are
capable of binding NRP-1. However, only RPPR and RPRR segments form an optimal organization around
loop III with low potential energy. In other analogs, the absence of these stabilizing interactions always
results in higher potential energy of the complexes. The binding of RPAR analogs does not guarantee
receptor activation; only stable complexes that are properly stabilized via loop III appear able to trigger
NRP-1 activati on |